This program is concerned with the exploration of new approaches leading to the development of more effective cancer therapy through the integrated and yet diversified contributions of various groups of existing and new laboratories of the Department of Experimental Therapeutics at Roswell Park. New compounds, synthesized within this program or obtained from outside sources, are being tested for biological activity in bacterial, viral and mammalian cell systems in vitro and in tumor-bearing rodents. The preclinical pharmacology of compounds of interest is being studied in several animal species prior to their initial clinical trial. Fundamental studies on the biochemical and pharmacological basis for selective cellular effects of drugs are being carried out in relation to the drug development activities in a variety of experimental systems and in man, and provide an important source of information leading to the design of additional drugs with improved selectivity of action. These biochemical and pharmacological studies include investigations on the changes in the regulation of cell metabolism involved in drug biotransformation, cell membrane function, carcinogenesis, and immunity to tumor, as well as studies on drug disposition, on the basis for drug toxicity to tumor and normal cells, and on kinetic factors, leading to the design of optimal combinations or schedules of treatment. In this program, development of new anticancer drugs and new forms of treatment is integrated closely with both basic progress in the biochemical pharmacology of anticancer drugs and fundamental studies on the regulation of cell metabolism; interactions among these approaches using both preclinical systems and human materials should provide an optimal background for the formulation of new ideas leading to advances in the therapy of cancer. BIBLIOGRAPHIC REFERENCES: Dave, C., Ehrke, J., and Mihich, E., Spectrophotometric Studies on the Binding with Polynucleotides of 4,4'-Diacetyldiphenylurea-bis(guanylhydrazone) and Methylglyoxal-bis(guanylhydrazone). Chem. Biol. Interactions 12:183-195, 1976. Mihich, E., Bernacki, R., Korytnyk, W. and Porter, C., Plasma Membrane Inhibitors and Modifiers. Proc. WHO Conference, Milan, Italy, 17-20 November 1975. In: Rational Design and Synthesis of Compounds for Cancer Chemotherapy, pg. 63, 1976.